This proposal consists of seven unrelated projects designed to prepare structurally novel, biologically active natural products of potential interest as drugs and to explore new synthetic methods of general interest. (1) The first synthesis of the novel pyrroloquinolines martinellic acid and martinelline will be completed. These alkaloids inhibit several G-protein coupled receptors. (2) New methods have been developed and used for the first syntheses of fumiquinazolines A, B, G, and I and asperlicin. This project will be completed by the synthesis of the more highly oxidized fumiquinazolines C, D, E, and H, fiscalins A and B, and citreoindole. (3) The novel diterpene antibiotic guanacastepene that appears to function by disruption of membranes will be prepared using a novel route to the hydroazulene ring system. This chemistry will be used for a short synthesis of the CD ring system of vitamin D. (4) Haterumalide B and haterumalide NA (oocydin A) are novel macrolides isolated from a sponge, ascidian and phytopathogen that are cytotoxic and show selective toxicity to breast cancer cells. An efficient route to these compounds using a Stille coupling of an allylic bromide or acetate with a vinylstannane to construct the skipped chlorodiene unit will be developed. (5) Cytoskyrin A, graciliformin, and rugulosin are unusual bisanthraquinoid natural products that have potent biological activity and structural novelty. They will be synthesized by a biogenetic route using a phenyldimethylsilyl group as a latent hydroxy group. (6) Phloeodictine A and Al-A7 area family of guanidine containing amidinium salt natural products that are cytotoxic and antibacterial. In model studies, a general new route to these compounds has been developed by adding Grignard reagents to the acyl group of an N-acylamidine and then alkylating the amidine. This will be extended to the natural products and analogues. (7) Mn(III)-based oxidative cyclization of Meldrum's acid derivatives occurs almost instantaneously at 25 degrees celcius to give predominantly cyclohexene products. The mechanism and synthetic utility of these cyclizations will be developed.